1. Field of the Invention
The present invention relates to pharmaceutical compositions and methods for the treatment of metabolic and cardiovascular disorders and to certain dichloroacetate derivatives as the active ingredients therein.
2. Discussion of the Prior Art
The pharmacologic and therapeutic properties of salts of dichloroacetic acid (DCA) have been extensively studied over the last several years [Stacpoole, Metabolism, Vol. 38, No. 11, pages 1124-1144 (1989)].
Researchers have found that DCA stimulates glucose uptake and utilization by peripheral tissues [Stacpoole et al, Metabolism, Vol. 19:71 (1970); McAllister et al, Biochem. J., Vol. 134:1067 (1973); Diamond et al, Diabetes, Vol. 31:326 (1982)] and inhibits hepatic glucose production [Stacpoole, Metabolism, Vol. 26:107 (1977); Demangre et al, Biochem. J., Vol. 172:91 (1978); Diamond et al, Metabolism, Vol. 30:880 (1981)]. It has also been found to decrease blood glucose levels in patients with diabetes mellitus [Stacpoole et al, N. Eng. J. Med., Vol. 298:526 (1978)]. DCA also stimulates 1actate oxidation in animal tissue and significantly decreases lactic acid levels and overall morbidity in patients with lactic acidosis [Stacpoole et al, N. Eng. J. Med., Vol. 309:390 (1983); Blackshear et al, Diabetes Care, Vol. 52391 (1982)]. In addition, DCA reduces circulating triglyceride and cholesterol concentrations in obese [Felts et al, Diabetes, Vol. 25 (suppl.):363 (1976)] and diabetic [Hayet et al, Metabolism, vol. 29:120 (1980); Riles et al, Diabetes, Vol. 28:852 (1979)] animals. DCA also markedly decreases blood cholesterol levels in patients with various forms of hyperlipidemia [Stacpoole et al, N. Eng. J. Med., Vol. 298:526 (1978); Moore et al, Atherosclerosis, Vol. 33:285 (1979)].
The efficacy of DCA for the treatment of metabolic disorders, however, is compromised by the fact that DCA is toxic to lower animals and humans, particularly upon chronic administration. It has been reported that a human patient who received DCA for about four months developed a mild polyneuropathy that resolved when treatment stopped [Moore et al, ibid]. Chronic administration of DCA to lower animals in doses exceeding those used clinically also induces a reversible peripheral neuropathy, changes in testicular morphology and lenticular opacities [Stacpoole, N. Eng. J. Med., Vol. 300:372 (1979)].
DCA is known to oxidize in vivo to glyoxalate and subsequently to oxalate [Demangre et al, Biochem. Biophys. Res. Comm., Vol. 8521180 (1978); Harris et al, Arch. Biochem. Biophys., Vol. 189:364 (1978) and Currey et al, Clin. Pharmacol. Ther., Vol. 37:894 (1985)]. Oxalate is a known neurotoxin [Bilbao et al, Can. J. Neurol. Sci., Vol. 3:63 (1976)] and cataract inducing chemical [Fielder et al, Br. J. Ophthal., Vol. 64:782 (1980)], and may be at least partly responsible for the neuropathic changes associated with the chronic administration of DCA.
The drug also improves cardiac output and left ventricular mechanical efficiency under conditions of myocardial ischemia or failure, probably by facilitating myocardial metabolism of carbohydrate and 1actate as opposed to fat. DCA may also enhance regional 1actate removal and restoration of brain function in experimental stages of cerebral ischemia [Stacpoole, Metabolism, ibid].
DCA appears to inhibit its own metabolism, which may influence the duration of its pharmacologic actions and lead to toxicity. DCA can cause a reversible peripheral neuropathy that may be related to thiamine deficiency and may be ameliorated or prevented with thiamine supplementation [Stacpoole, Metabolism, ibid].
Carbicarb.TM. is a substantially equimolar mixture of sodium carbonate (Na.sub.2 CO.sub.3) and sodium bicarbonate (NaHCO.sub.3) which buffers solutions thereof to bicarbonate ions without a net generation of CO.sub.2. The mixture has been employed in humans and animals to restore normal systemic (blood) and/or intracellular pH and acid-base status which results in an improvement in the metabolism and function of cells, tissues and organisms [Filley et al, Trans. Am. Clin. Clinatol Assoc., vol. 96, page 141 (1934); Whalen et al, Clin. Res., Vol. 36, page 374A (1988); and Betsin et al, Circulation, Vol. 77, page 227 (1988)].
It is an object of the present invention to provide novel compositions and methods for the safe and effective treatment of certain metabolic and/or cardiovascular disorders which synergistically combine the therapeutic properties of Carbicarb.TM. or similar carbonate/bicarbonate buffering systems and DCA.